(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property Organization
International Bureau
(43) International Publication Date
7 February 2002 (07.02.2002)
PCT
(10) International Publication Number
WO 02/10728 Al
(51) International Patent Classification 7 : COIN 21/86,
33/49
(21) International Application Number: PCT/US0 1/21766
(22) International Filing Date: 9 July 2001 (09.07.2001)
(25) Filing Language: English
(26) Publication Language: English
(30) Priority Data:
09/630,340
3 1 July 2000 (3 1 .07.2000) US
(71) Applicant: LIFESCAN, INC. [US/US]; 1000 Gibraltar
Drive, Milpitas, CA 95035-6312 (US).
(72) Inventors: PAN, Victor; 1101 Quema Drive, Fremont,
CA 94539 (US). LEMKE, John; 7833 Flagstone Drive,
Pleasanton, CA 94588 (US). PATEL, Harshad, I.; 45102
Cougar Circle, Fremont, CA 94539 (US). CIZDZIEL,
Philip; 2054 Stonewood Lane, San Jose, CA 95132 (US).
(74) Agent: FIELD, Bret, E.; Bozicevic, Field & Francis, LLP,
Suite 200, 200 Middlefield Road, Menlo Park, CA 94025
(US).
(81) Designated States (national): AE, AG, AL, AM, AT, AU,
AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
CZ, DE, DK, DM, DZ, EC, EE, ES, FT, GB, GD, GE, GH,
GM, HR, HU, ID, 1L, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, .
SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW.
(84) Designated States (regional): ARIPO patent (GH, GM,
KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE,
IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
Published:
— with international search report
— before the expiration of the time limit for amending the
claims and to be republished in the event of receipt of
. - * amendments
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.
qq (54) Title: METHOD AND APPARATUS FOR DETECTING THE PRESENCE OF A FLUID ON A TEST STRIP
(57) Abstract: Methods and devices are provided for detecting the application of a fluid sample onto a test strip surface when the test
^ strip is inserted into an optical meter. In the subject methods, reflectance data is obtained from a portion of the optical meter in which
^ the sample application region of the test strip is located, where the reflectance data covers a period of time ranging from a point at
W least prior to application of the sample to the strip to a point following application of the sample to the strip. The presence of the fluid
sample on the test strip is then determined from the reflectance data. Also provided are optical meters that include optical means for
Q obtaining reflectance data, where these optical means include at least an irradiation source and a light detector. The subject methods
and devices find use with a variety of test strips, and are particularly suited for use with test strips that include a fluid movement
^ means, such as a compressible bladder.
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WO 02/10728 PCT/US01/21766
METHOD AND APPARATUS FOR DETECTING THE
PRESENCE OF A FLUID ON A TEST STRIP
INTRODUCTION
Field of the Invention
The field of this invention is fluidic medical diagnostic devices for measuring the
concentration of an analyte in or a property of a biological fluid.
Description of the Specific Embodiments
A variety of medical diagnostic procedures involve tests on biological fluids, such as
blood, urine, or saliva, and are based on a change in a physical characteristic of such a fluid or an
element of the fluid, such as blood serum The characteristic can be an electrical, magnetic, fluidic,
15 or optical property. When an optical property is monitored, these procedures may make use of a
transparent or translucent device to contain the biological fluid and a reagent. A change in light
absorption, reflection, or scattering of the fluid can be related to an analyte concentration in, or
property o£ the fluid.
Of increasing use in many of the above described diagnostic procedures is the use of assay
20 systems made up of disposable test cards or strips and meters for reading these strips. In many of
the test cards or strips employed in these systems, fluid is introduced into the strip at one location,
e.g. a sample application site, but analyzed at another, e.g. a measurement site. In such devices, -
movement of the introduced fluid from the sample application site to the measurement site is
necessary. As such, these devices require a means for moving fluid from the sample application site
25 to the measurement site.
In one class of fluidic test cards or strips that find use in the above described assay systems,
fluid is moved through the device from the site of introduction by negative pressure, where the
negative pressure is typically provided by a compressible bladder. Such devices include those
described in U. S. Patent 3,620,676; U.S. Patent 3,640,267 and EP 0 803 288. In these types of
30 devices, the bladder must be compressed prior to application of the sample to the sample
application site of the test strip and then decompressed following application of the sample to the
sample application site.
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Of interest for use in the above described systems would be a meter that is capable of
automatically actuating the bladder of a test strip in a correct and reproducible manner during use.
As such, of interest is the development of a meter that is capable of identifying the application of a
fluid sample onto a test strip and actuating a bladder in a correct manner in response thereto.
5 Relevant Literature
References of interest include: U.S. Patent Nos.: 3,620,676; 3,640,267; 4,088,448;
4,420,566; 4,426,451; 4,868,129; 5,049,487; 5,104,813; 5,230,866; 5,627,04; 5,700,695;
5,736,404; 5,208,163; 5,708,278 and European Patent Application EP 0 803 288.
10 SUMMARY OF THE INVENTION
Methods and devices are provided for detecting the application of a fluid sample onto
a test strip. In the subject methods, reflectance data is obtained from a portion of an optical
meter in which the sample application region of the test strip is located, where the reflectance
data covers a period of time ranging from a point at least prior to application of the sample to
15 the strip to a point following application of the sample to the strip. The application of the
fluid sample onto the test strip is then determined from the reflectance data. Also provided are
optical meters that include optical means for obtaining reflectance data, where these optical
means include at least an irradiation source and a light detector. The subject methods and
devices find use with a variety of test strips, and are particularly suited for use with test strips
20 that include a fluid movement means, such as a compressible bladder.
BRIEF DESCRIPTION OF THE FIGURES
Fig. 1 is a plan view of a test strip with which the subject methods and devices find use.
Fig. 2 is an exploded view of the device of Fig. 1.
25 Fig. 3 is a perspective view of the device of Fig. 1 .
Fig. 4 is a schematic of a meter for use with a device of this invention.
Fig. 5 is a graph of data that is used to determine PT time. .
Figs. 6A to 6E provide a sequential representation of the sample application detection
method of the subject inventioa
30
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DESCRIPTION OF THE SPECIFIC EMBODIMENTS
Methods and devices are provided for detecting the application of a fluid sample onto
a test strip. In the subject methods, reflectance data is obtained from a portion of an optical
meter in which the sample application region of the test strip is located, where the reflectance
5 data covers a period of time ranging from a point at least prior to application of the sample to
the strip to a point following application of the sample to the strip. The application of the
fluid sample onto the test strip surface is then determined from the reflectance data. Also
provided are optical meters that include optical means for obtaining reflectance data, where
these optical means include at least an irradiation source and a light detector. The subject
10 methods and devices find use with a variety of test strips, and are particularly suited for use
with test strips that include a fluid movement means, such as a compressible bladder. In
further describing the subject invention, the subject methods will be discussed first in greater
detail followed by a description of the assay systems and components thereof that are used to
practice the subject methods.
15
Before the subject invention is described further, it is to be understood that the
invention is not limited to the particular embodiments of the invention described below, as
variations of the particular embodiments may be made and still fall within the scope of the
appended claims. It is also to be understood that the terminology employed is for the purpose
20 of describing particular embodiments, and is not intended to be limiting. Instead, the scope of
the present invention will be established by the appended claims.
In this specification and the appended claims, singular references include the plural,
unless the context clearly dictates otherwise. Unless defined otherwise, all technical and
25 scientific terms used herein have the same meaning as commonly understood to one of
ordinary skill in the art to which this invention belongs.
METHODS
As summarized above, the subject invention provides methods for detecting the
30 application of a fluid sample onto a test strip surface when the test strip is placed in a meter,
generally an optical meter. In other words, the subject methods provide a means for
determining the application of a fluid sample to a surface of a test strip. As such, the subject
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methods are at least able to provide data regarding whether or not a fluid sample has been
placed onto an application site of a test strip when the test strip is present in an optical meter.
In many embodiments, the subject methods are also capable of detecting the application of a
minimal or threshold amount of sample to the test strip surface, and in certain embodiments
5 are capable of determining the amount of fluid that has been applied to the test strip.
In practicing the subject methods, reflectance data from the test strip is first obtained,
where the reflectance data is then employed to at least determine whether sample has been
applied to the test strip, where the reflectance data often yield information concerning
whether a threshold amount of sample has been applied to the test strip surface. By
10 reflectance data is meant a series of reflectance values obtained over a period of time. By
reflectance value is meant an observed amount of reflected light, where the reflected light may
be specular and/or diffusely reflected light, and is often both specular and diffusely reflected
light.
The period of time over which the reflectance values are determined in order to obtain
15 the requisite reflectance data at least ranges from a point prior to application of sample to the
surface of a test strip to a point following application of the sample to a test strip, where in
certain embodiments the period of time commences following introduction of the test strip
into the optical meter and in certain other embodiments the period of time ranges from a point
prior to introduction of the test strip into the optical meter to a point after application of the
20 sample to the test strip present in the meter. As such, the period of time over which
reflectance values are measured in obtaining the requisite reflectance data generally ranges
from about 1 minute to 2 minutes, usually from about 20 seconds to 30 seconds and more
usually from about 3 second to 5 seconds. In obtaining the requisite reflectance data,
reflectance values may be obtained periodically or substantially continuously, if not
25 continuously, during the period of time. Where the reflectance values are obtained
periodically, these values will be obtained a minimum number of times, where the minimum
number is generally at least about 1 reading per second, usually at least about 2 readings per
second and more usually at least about 4 readings per second. In many of these embodiments,
the number of reflectance values that are obtained over a given period of time ranges from
30 about 60 to 120, usually from about 40 to 60 and more usually from about 12 to 20.
The above described reflectance data may be obtained using any convenient protocol.
In many embodiments of the subject invention, the reference data is obtained by irradiating a
WO 02/10728 PCT7US01/21766
region of the optical meter occupied by the sample application site of the test strip when
inserted into the meter and detecting reflected light, both specular and difluse, from the
region over the desired period of time. In these protocols, the specific region of the optical
meter that is irradiated is a region of the optical meter occupied by a bottom surface of the
5 test strip opposite the sample application site when the strip inserted into the meter is
irradiated. The region is generally irradiated with light over a narrow range of wavelengths. In
many embodiments, the wavelengths of light that are used to irradiate the region of the
optical meter ranges from about 400nm to 700nm, usually from about 500nm to 640nm and
more usually from about 550nm to 590nm.
10 As mentioned above, in obtaining the reflectance data, one may periodically obtain
reflectance values over the above described period of time or obtain reflectance values
substantially continuously, if not continuously, over the above described period of time. As
mentioned above, the period of time over which reflectance values are obtained in order to
produce the requisite reflectance data ranges from a point prior to insertion of the test strip
15 , into the meter to a point following application of the sample to the application site of the test
strip inserted into the meter. In these embodiments, the following protocol is generally
employed.
First, the region of the optical meter occupied by the application site of the test strip is
irradiated with light over a narrow range of wavelengths and reflected light (or generally the
20 absence thereof) is detected one or more times, including continuously, during this first step.
The length of time for this first step ranges from about 250ms to 1 second, usually from about
250ms to 750ms and more usually from about 250ms to 500ms. . Next, a test strip is inserted
into the meter while the portion of the meter continues to irradiated and reflected light from
the bottom surface of the test strip is detected one or more times, including continuously,
25 during this second step. The length of time for this second step ranges from about 500ms to
2 minutes, usually from about 500ms to 1 minute and more usually from about 500ms to
750ms. Next, sample is applied to the sample application site of the test strip, while the
portion of the meter continues to irradiated and reflected light from the bottom surface of the
test strip is detected one or more times, including continuously, during this third step. The
30 length of time for this third step typically ranges from about 250ms to 1 second, usually from
about 250ms to 750ms and more usually from about 250ms to 500ms. Finally, the region of
the meter continues to be irradiated following application of the sample and reflectance values
WO 02/10728 PCT/US01/21766
obtained one or more times, including continuously, until the end of the above described time
period is reached. The length of time for this last step typically ranges from about 500ms to 3
second, usually from about 500ms to 2 seconds and more usually from about 500ms to 1
second.
5 Once the above described reflectance data is obtained, it is compared to a reference in
order to at least determine whether or not sample has been applied to the sample application
site of the test strip, where in certain embodiments this comparison step yields information
regarding whether a minimum or threshold amount of sample has been applied to the sample
application site of the test strip. By reference is meant a data set or processed form thereof
10 that indicates sample application onto a test strip surface, and in many embodiments the
application of at least a threshold amount of sample. The reflectance data may or may not be
processed prior to comparison with the reference, depending on the particular nature of the
reference. Thus, in certain embodiments, the reflectance data is compared in raw form to the
reference, where the reference is also present in a corresponding raw form of numerical
15 values, e.g. reflectance amplitude vs. time. Alternatively, the reflectance data may be
processed into a graph of reflectance over time, where the reference is a similar graph, and
the two graphs may be compared. This comparison step may be performed manually or by a
suitable automated data processing means, e.g. a computing means made up of suitable
computing hardware and software. The above comparison step yields a sample present
20 signal. In other words, following the above comparison, one obtains a reading as to whether
sample has been applied to the test strip surface, and often whether a threshold amount of the
sample is present on the step strip surface.
Systems
25 As summarized above, the above described methods find use with systems that are
made up of disposable test strips and optical meters for reading these test strips. Each of these
system components is now described in greater detail.
Test Strips
30 The test strips of the systems are fluidic devices that generally include a sample application
area; a bladder, to create a suction force to draw the sample into the device; a measurement area,
in which the sample may undergo a change in an optical parameter, such as light scattering; and a
WO 02/10728 . PCT/US01/21766
stop junction to precisely stop flow after filling the measurement area. Preferably, the test strips are
substantially transparent over the measurement area, so that the area can be illuminated by a light
source on one side and the transmitted light measured on the opposite side. Furthermore, at least
the bottom surface of the test strip is non-porous.
5 A representative bladder including test strip is shown in Figs. 1 , 2 and 3 . Fig. 1 provides a
plan view of representative device 10, while Fig. 2 provides an exploded view and Fig. 3 provides
a perspective view of the same representative device. Sample is applied to sample port 12 after
bladder 14 has been compressed. Clearly, the region of layer 26 and/or layer 28 that adjoins the
cutout for bladder 14 must be resilient, to permit bladder 14 to be compressed. Polyester of about
10 0. 1 mm thickness has suitable resilience and springiness. Preferably, top layer 26 has a thickness of
about 0. 125 mm, bottom layer 28 about 0. 100 mm. When the bladder is released, suction draws
sample through channel 16 to measurement area 18, which preferably contains a reagent 20. In
order to ensure that measurement area 18 can be filled with sample, the volume of bladder 14 is
preferably at least about equal to the combined volume of channel 16 and measurement area 18. If
1 5 measurement area 1 8 is to be illuminated from below, layer 28 must be transparent where it
adjoins measurement area 18.
As shown in Figs. 1, 2, and 3, stop junction 22 adjoins bladder 14 and measurement area
18; however, a continuation of channel 16 may be on either or both sides of stop junction 22,
separating the stop junction from measurement area 18 and/or bladder 14. When the sample
20 reaches stop junction 22, sample flow stops. The principle of operation of stop junctions is
described in U.S. Patent 5,230,866, incorporated herein by reference.
As shown in Fig. 2, all the above elements are formed by cutouts in intermediate layer 24,
sandwiched between top layer 26 and bottom layer 28. Preferably, layer 24 is double-sided
adhesive tape. Stop junction 22 is formed by an additional cutout in layer 26 and/or 28, aligned
25 with the cutout in layer 24 and sealed with sealing layer 30 and/or 32. Preferably, as shown, the
stop junction comprises cutouts in both layers 26 and 28, with sealing layers 30 and 32. Each
cutout for stop junction 22 is at least as wide as channel 16, Also shown in Fig. 2 is an optional
filter 12A to cover sample port 12. The filter may separate out red blood cells from a whole blood
sample and/or may contain a reagent to interact with the blood to provide additional information.
30 A suitable filter comprises an anisotropic membrane, preferably a polysulfone membrane of the
type available from Spectral Diagnostics, Inc., Toronto, Canada Optional reflector 18Amay be
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WO 02/10728 PCT7US01/21766
on, or adjacent to, a surface of layer 26 and positioned over measurement area 18. If the reflector
is present, the device becomes a transflectance device.
The device pictured in Fig. 2 and described above is preferably formed by laminating
thermoplastic sheets 26 and 28 to a thermoplastic intermediate layer 24 that has adhesive on both
5 of its surfaces. The cutouts that form the elements shown in Fig. 1 may be formed, for example,
by laser- or die-cutting of layers 24, 26, and 28. Alternatively, the device can be formed of molded
plastic. Preferably, the surface of sheet 28 is hydrophilic. (Film 9962, available from 3M, St. Paul,
MN.) However, the surfaces do not need to be hydrophilic, because the sample fluid will fill the
device without capillaiy forces. Thus, sheets 26 and 28 may be untreated polyester or other
10 thermoplastic sheet, well known in the art. Similarly, since gravity is not involved in filling, the
device can be used in any orientation. Unlike capillary fill devices that have vent holes through
which sample could leak, these types of devices vent through the sample port before sample is
applied, which means that the part of the strip that is first inserted into the meter is without an
opening, reducing the risk of contaminatioa
15 Other fluidic device configurations are also possible, where such alternative device
configurations include those that have: (a) a bypass channel; (b) multiple parallel measurement
areas; and/or (c) multiple in series measurement areas; etc. In addition, the above described
laminated structures can be adapted to injection molded structures.
20 Meters
The optical meters of the subject systems at least include a means for collecting
reflectance data from a region of the optical meter that is occupied by a sample application
location of a test strip when the test strip is present in the meter. This means for collecting
reflectance data is generally made up of a light source and a detector. The light source is a
25 source of visible light that is capable of irradiating or illuminating the region of the optical
meter with light over a narrow range of wavelengths, where the wavelengths typically ranges
from about 400nm to 700nm, usually from about 500nm to 640nm and more usually from
about 550nm to 590nnoL Any convenient light source may be employed, where suitable light
sources include: LED, laser diode, filtered lamp and the like. Also part of the means for
30 collecting reflectance data is a suitable detector that is capable of detecting reflected light, e.g.
specular and/or diffusely reflected, from the region of the optical meter and then converting
the collected light to an electrical signal. Any convenient detector may be employed, where
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WO 02/10728 PCT/US01/21766
suitable detectors include: photodiode, photodetector, phototransistor and the like.
Preferably, the detection system is AC-modulated to provide immunity from the ambient
noise and interference during use. In this implementation, the light source is turned on and
off ("chopped") at 2000Hz. The smaller signal of interest from the detector, in the presence
5 of much larger amplitude fluctuating noise, has the form of a square wave due to the
modulating light source. The "chopped" signal with its noise is amplified and connected to
the input of a synchronous detector. The synchronous detector consists of an integrating
analog to digital converter (ADC) and a reference signal with the exact frequency and phase
as the chopped light source. When the light source is on, the signal is integrated; when the
10 light source is off; the integrator sits idle. The detection system can integrate the signal for a
specified amount of time or take multiple average readings to reduce noise. A spectral
blocking filter may also be included over the detector to reduce interference from ambient
light.
In addition to the above means for obtaining reflectance data, the subject meters also
15 generally include a means for comparing the reflectance data to a control value reference, as
described above, to obtain a sample present signal. This means is generally a data processing
means, such as a computing means made up of appropriate computing hardware and
software, for comparing the reference data to the reference and generating a sample present
signal.
20 The subject devices also generally include a means for actuating a bladder on the
device in response to the sample present signal. Any convenient actuation means may be
present, so long as it is capable of decompressing the bladder in response to the sample
present signal.
A representative meter is depicted in Fig. 4, where a representative test strip 10 is inserted
25 into the meter. The meter shown in Fig. 4 includes strip detector 40 (made up of LED 40a and
detector 40b), sample detector 42 (made up of light source 42a and detector 42b as described
above), measurement system 44 (made up of LED 44a and detector 44b), and optional heater 46.
The device further includes a bladder actuator 48. The bladder actuator is actuated by the strip
detector 40 and the sample detector 42, as described above, such that when a strip is inserted into
3 0 the meter and detected by the strip detector, the bladder actuator is depressed, and when the
sample is added to the fluidic device or strip inserted into the meter, the bladder actuator is
withdrawn so as to decompress the bladder and concomitantly pull sample into the measurement
WO 02/10728
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area of the device via the resultant negative pressure conditions. Also present is a meter display 50
that provides for an interface with the user.
Methods of Use
5 The above described sample detection methods and systems including the same, where
the systems include the test strip holders and the subject meters, are suitable for use in a
variety of analytical tests of biological fluids, such as determining biochemical or
hematological characteristics, or measuring the concentration in such fluids of analytes such
as proteins, hormones, carbohydrates, lipids, drugs, toxins, gases, electrolytes, etc. The
10 procedures for performing these tests have been described in the literature. Among the tests,
and where they are described, are the following: (1) Chromogenic Factor Xlla Assay (and
other clotting factors as well): Rand, M.D. et al, Blood, 88* 3432 (1996); (2) Factor X
Assay: Bick,RX. Disorders of Thrombosis and Hemostasis: Clinical and Laboratory
Practice. Chicago, ASCP Press, 1992.; (3) DRWT (Dilute Russells Viper Venom Test):
1 5 Exner, T. et al., Blood Coag. Fibrinol., L 259 (1990); (4) Immunonephelometric and
Lnmunotuibidimetric Assays for Proteins: Whicher, J.T., CRC Crit. Rev. Clin Lab Sci. 18:213
(1983); (5) TPA Assay: Mann, KG, et al, Blood, 76, 755, (1990).; and Hartshorn, J.N. et al.,
Blood, 78, 833 (1991); (6) APTT (Activated Partial Thromboplastin Time Assay): Proctor, RJL
and Rapaport, SI Amer. J. Clin. Path, 36, 212 (1961); Brandt, J.T. and Triplett, DA Amer. J.
20 Clin. Path., 76, 530 (1981); and Kelsey, P.R. Thromb. Haemost 52, 172 (1984); (7) HbAlc
Assay (Glycosylated Hemoglobin Assay): Nicol, DJ. et al., Clin. Chem. 29, 1694 (1983); (8)
Total Hemoglobin: Schneck et al., Clinical Chem., 32/33. 526 (1986); and U.S. Patent 4,088,448;
(9) Factor Xa: Vinazzer, H., Proc. Symp. Dtsch. Ges. Klin. Chem., 203 (1977), ed. By Witt,
1^(10) Colorimetric Assay for Nitric Oxide: Schmidt, HH, et al, Biochemica, 2, 22 (1995).
25 The above described fluid device/meter systems are particularly well suited for measuring
blood-clotting time - "prothrombin time" or "PT time, " as more fully described in Application
Serial Nos. 09/333765, filed June 15, 1999; and 09/356248, filed July 16, 1999, the disclosures of
which are herein incorporated by reference. The modifications needed to adapt the device for
applications such as those listed above require no more than routine experimentation.
30 In using the above systems that include the subject sample application detection means, the
first step the user performs is to turn on the meter, thereby energizing strip detector 40, sample
detector 42, measurement system 44, and optional heater 46. The region of the meter that is
10
WO 02/10728 PCT/US01/21766
occupied by the portion of the test strip that includes the sample application site is then irradiated
with light from light source 42a and the detector detects little or no reflected light, thereby
providing for a base reading, as shown in Fig. 6A Next, test strip 10 is inserted through the
opening of the meter and into the device. Preferably, the strip is not transparent over at least a part
5 of its area, so that an inserted strip will block the illumination by LED 40a of detector 40b. (More
preferably, the intermediate layer is formed of a non-transparent material, so that background light
does not enter measurement system 44.) Detector 40b thereby senses that a strip has been inserted
and triggers bladder actuator 48 to compress bladder 14. In addition, detector 42b detects a signal
as shown in Fig. 6B which is used to establish a "before" reading. A meter display 50 then directs
10 the user to apply a sample to sample port 12 as the third and last step the user must perform to
initiate the measurement sequence. When a sample is introduced into the sample port as shown in
Fig. 6C, more light is reflected to detector 42b. Following sample application, light detector 42b
continues to detect light as shown in Fig. 6D in order to establish an after reading. In Fig. 6D, the
radiation from the light source is absorbed 62 by the sample 60 and the reflected ray is reduced due
15 to index matching at the sample fluid/ film interface 64. The observed decrease in reflectance
reading is related to index-matching at the sample fluid to strip interface. Fig. 6E provides atypical
output signal of the detected sample application process described above. The reflectance data as
represented in Fig. 6E is then compared to a reference to obtain a sample present signal, which
sample present signal, in turn, signals bladder actuator 48 to release bladder 14. The resultant
20 ' suction in channel 16 draws sample through measurement area 18 to stop junction 22. Light from
LED 44a passes through measurement area 18, and detector 44b monitors the light transmitted
through the sample as it is clotting. Analysis of the transmitted light as a function of time (as
described below) permits a calculation of the PT time, which is displayed on the meter display 50.
Preferably, sample temperature is maintained at about 37°C by heater 46.
25 Fig. 5 depicts a typical "clot signature" curve in which the output from assay detector 44b
is plotted as a function of time. Blood is first detected in the measurement area by 44b at time 1 .
In the time interval A, between points 1 and 2, the blood fills the measurement area. The reduction
in output during that time interval is due to light scattered or absorbed by red cells and is thus an
approximate measure of the hematocrit. At point 2, sample has filled the measurement area and is
30 at rest, its movement having been stopped by the stop junction. The red cells begin to stack up
like coins (rouleaux formation). The rouleaux effect allows increasing light transmission through
the sample (and less scattering) in the time interval between points 2 and 3. At point 3, clot
11
WO 02/10728 PCT7US01/21766
formation ends rouleaux formation and transmission through the. sample reaches a maximum. The
PT time can be calculated from the interval B between points 1 and 3 or between 2 and 3.
Thereafter, blood changes state from liquid to a semi-solid gel, with a corresponding reduction in
light transmissioa The reduction in output C between the maximum 3 and endpoint 4 correlates
5 with fibrinogen in the sample.
It is evident from the above results and discussion that the above describe invention
provides a simple and accurate way to identify when a fluid sample has been applied to a test
strip. The above described invention provides for a number of advantages, including: (a) the
10 ability to differentiate between fluid sample applied to a test strip and other false trigger
events, such as shadows or reflections caused by the finger or other application devices near
the application area; (b) the ability to determine that minimum sample volume has been added
to the test strip to ensure that air is not drawn into the strip by accident upon actuation; (c)
the ability to operate under ambient lighting conditions with little or no light shield. As such,
1 5 the subject invention represents a significant contribution to the art.
All publications and patents cited in this specification are herein incorporated by
reference as if each individual publication or patent were specifically and individually
indicated to be incorporated by reference. The citation of any publication is for its disclosure
20 prior to the filing date and should not be construed as an admission that the present invention
is not entitled to antedate such publication by virtue of prior invention.-
Although the foregoing invention has been described in some detail by way of
illustration and example for purposes of clarity of understanding, it is readily apparent to
25 those of ordinary skill in the art in light of the teachings of this invention that certain changes
and modifications may be made thereto without departing from the spirit or scope of the
appended claims.
12
WO 02/10728
WHAT IS CLAIMED TS:
PCT/US01/21766
1. A method for detecting the application of a fluid sample onto a non-porous test strip
in an optical meter, said method comprising:
5 (a) obtaining reflectance data from a bottom side of said test strip opposite a fluid
sample application site for a period ranging from a time prior to application of said fluid
sample to said fluid sample application site to a time after application of said fluid sample to
said fluid sample application site; and
(b) deriving from said reflectance data the application of said fluid sample onto
10 said test strip. '
2. The method according to Claim 1, wherein said method comprises irradiating said
bottom side of said test strip with visible light during said period.
15 3 . The method according to Claim 2, wherein said visible light is of a narrow range of
wavelengths.
4. The method according to Claim 3, wherein said wavelengths range from about 550 to
590 nm.
20
5. The method according to Claims 1, 2, 3 or 4 5 wherein said non-porous test strip is
fabricated from a polymeric material.
6. The method according to any of the preceding claims, wherein said reflectance data is
25 obtained by the method comprising:
(i) introducing a test strip into said optical meter and irradiating a portion of said
optical meter occupied by a bottom side of said test strip when said test strip is inserted into ,
said meter with light of narrow range of wavelength;
(ii) applying a fluid sample to said test strip while continuing to irradiate said
30 portion; and
(iii) collecting reflected light from said portion during said steps (i) and (ii) for a
period after said step (ii) to obtain said reflectance data.
13
WO 02/10728 PCT/US01/21766
7. The method according to any of the preceding claims, wherein the fluid sample is a
physiological sample.
8. The method according to Claim 7, wherein said physiological sample is blood.
9. An optical meter that can determine when sample has been applied to the surface of a
test strip inserted into it, said meter comprising:
(a) an element for collecting reflectance data from a region of said meter occupied
by a sample application location of said test strip when present in said meter, wherein said
means comprises:
(i) a light source for irradiating said region of said meter; and
(ii) a detector for detecting reflected light from said region of said meter,
(b) an element for comparing said reflectance data to a reference value to obtain a
sample present signal; and
(c) an element for actuating a fluid sample movement means of said test strip in
response to said sample present signal.
10. The optical meter according to Claim 9, wherein said light source is a source of visible
light.
11. The optical meter according to Claims 9 or 1 0, wherein said meter further comprises
said test strip.
12. The optical meter according to Claims 9, 10 or 11, wherein said fluid movement
actuator element is a bladder depressing means.
14
WO 02/10728
PCT/US01/21766
1/7
FIG. 1
WO 02/10728 PCT/US01/21766
2/7
WO 02/10728 PCT/US01/21766
3/7
FIG. 3
WO 02/10728
PCT/US01/21766.
4/7
WO 02/10728
PCT/US01/21766
5/7
TIME
WO 02/10728
PCT/USO 1/21766
6/7
FIG6A
42a
42b
WO 02/10728
PCT/US01/21766
INTERNATIONAL SEARCH REPORT
International Application No
PCT/US 01/21766
A. CLASSIFICATION OF SUBJECT MATTER
IPC 7 G01N21/86 G01N33/49
According lo International Patent Classification (IPC) or to bolh national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
IPC 7 601N
Documentation searched other than minimum documentation to the extent that such documents are included In Ihe fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
EPO-Internal
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category • Citation of document, with Indication, where appropriate, of the relevant passages
Relevant to claim No.
EP 0 974 840 A (LIFESCAN INC)
26 January 2000 (2000-01-26)
column 7, line 41 -column 8, line 42;
figure 4
EP 1 069 427 A (LIFESCAN INC)
17 January 2001 (2001-01-17)
column 8, line 27 -column 9, line 20;
claims 1-5; figures 4,5
US 5 508 521 A (GODLEVSKI GREGORY S ET
AL) 16 April 1996 (1996-04-16)
column 1, line 10 - line 22
column 2, line 50 -column 4, line 25;
figures 1-3
-/-
1-12
1-12
1-8
m
Further documents are listed in the continuation of box C.
ID
Patent family members are listed in annex.
° Special categories of cited documents :
"A" document defining the general state of the art which is not
considered to be of particular relevance
"E" earlier document but published on or after the International
filing date
'V document which may throw doubts on priority ctalm(s) or
which Is cited to establish the publication date of another
citation or other special reason (as specified)
"C/ document referring to an oral disclosure, use, exhibition or
other means
•p' document published prior lo the international filing date but
later than the priority date claimed
'V later documenl published after the international filing date
or priority date and not in conflict with the application but
cited to understand the principle or theory underlying the
invention
•X' document of particular relevance; the claimed invention
cannot be considered novel or cannot be considered to
Involve an inventive step when the document Is taken alone
•Y* document of particular relevance; the claimed Invention
cannot be considered to involve an invenlfve step when (he
document Is combined with one or more other such docu-
ments, such combination being obvious to a person skilled
In the art
document member of the same patent family
Date of the actual completion of the international search
14 November 2001
Date of mailing of the international search report
18/12/2001
Name and mailing address of the ISA
European Patent Office, P.B. 5818 Palentlaan 2
NL-2280HVRijswiJk
TeL (+31-70) 340-2040. Tx. 31 651 epo nL .
Fax (+31-70) 340-3018
Authorized officer
Tabellion, H
Form PCTflSA/210 (second sheet) (July 1992)
INTERNATIONAL SEARCH REPORT
International Application No
PCT/US 01/21766
C.(Continuatlon) DOCUMENTS CONSIDERED TO BE RELEVANT
Category '
Citation of document, with Indicatlon.where appropriate, of the relevant passages
Relevant to claim No.
x •
US 4 849 340 A (OBERHARDT BRUCE)
18 July 1989 (1989-07-18)
column 9, line 43 -column 10, line 30;
figures 1-4
EP 0 922 954 A (UMM ELECTRONICS INC)
16 June 1999 (1999-06-16)
abstract
WO 99 18426 A (TAJNAF0I GABOR ;77
ELEKTRONIKA HUSZERIPARI KFT (HU))
15 April 1999 (1999-04-15)
abstract
1,5
Form PCT/1SA/210 (continuation of second sheet) (July 1992)
INTERNATIONAL SEARCH REPORT
Information on patent family members
International Application No
PCT/US 01/21766
Patent document
cited In search report
Publication
date
Patent family
member(s)
Publication
date
EP 0974840
26-01-2000
AU 4017299 A
CN 1250160 A
EP 0974840 A2
OP 2000055911 A
NO 993536 A
TW 411268 B
US 6084660 A
US 6261519 Bl
10- 02-
12-04-
26-01-
25-02-
21-01-
11- 11-
04-07-
17-07-
2000
2000
2000
2000
2000
2000
•2000
2001
EP 1069427 A 17-01-2001 US 6084660 A 04-07-2000
CN 1281146 A 24-01-2001
EP 1069427 A2 17-01-2001
OP 2001041957 A 16-02-2001
US 5508521 A 16-04-1996 CA 2251660 Al 23-10-1997
WO 9739335 Al 23-10-1997
AU 715230 B2 20-01-2000
AU 5712196 A 07-11-1997
EP 0894260 Al 03-02-1999
JP 2000509143 T 18-07-2000
US 4849340 A 18-07-1989
AT
120543
T
15-04-1995
AU
613623
B2
08-08-1991
AU
1591888
A
02-11-1988
CA
1310566
Al
24-11-1992
DE
3853457
Dl
04-05-1995
DE
3853457
T2
26-10-1995
EP
0308494
Al
29-03-1989
OP
1502797
T
28-09-1989
OP
2736091
B2
02-04-1998
WO
8807666
Al
06-10-1988
US
5110727
A
05-05-1992
US
5658723
A
19-08-1997
us
6197494
Bl
06-03-2001
EP 0922954
A
16-
-06-1999
US
6069011 A
30-05-2000
EP
0922954 A2
16-06-1999
WO 9918426
A
15-
-04-1999
HU
9701607 A2
28-07-1999
AU
9553998 A
27-04-1999
EP
1019706 Al
19-07-2000
WO
9918426 Al
• 15-04-1999
Form PCT/ISA/210 (palenl family annex) (July 1892)
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